Protein phosphatase 1 and phosphatase 1 nuclear targeting subunit-dependent regulation of DNA-dependent protein kinase and non-homologous end joining.
Protein phosphatase 1 and phosphatase 1 nuclear targeting subunit-dependent regulation of DNA-dependent protein kinase and non-homologous end joining.
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DOI：
10.1093/nar/gkx686
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发表时间：
2017-10-13
影响因子：
14.9
通讯作者：
Peng A
中科院分区：
文献类型：
--
作者：
Zhu S;Fisher LA;Bessho T;Peng A
DNA依赖性蛋白激酶催化亚基（DNA-PKcs）在介导非同源末端连接（NHEJ）（DNA双链断裂（DSB）的主要修复途径）中发挥关键作用。DNA-PKcs的活化、功能和动力学主要受其在许多残基处的可逆磷酸化调节，其中许多残基是DNA-PKcs本身靶向的。有趣的是，这些DNA-PKcs磷酸化位点以不同的，有时是相反的方式发挥作用，表明它们通过激酶和磷酸酶的复杂作用进行差异调节。在这项研究中，我们确定了几个磷酸酶亚基作为潜在的DSB相关蛋白。特别是，蛋白磷酸酶1（PP 1）被招募到非洲爪蟾卵提取物中的DSB模拟底物和人类细胞中激光微照射的位点。在爪蟾卵提取物和人类细胞中，PP 1的消耗损害NHEJ。PP 1结合DNA-PKcs的多个基序，调节DNA-PKcs磷酸化，并且是DNA损伤后DNA-PKcs活化所必需的。有趣的是，磷酸酶1核靶向亚基（PNUTS），PP 1的抑制性调节剂，也被招募到DNA损伤位点，以促进NHEJ。PNUTS与DNA-PK复合物结合，是DNA-PKcs在Ser-2056和Thr-2609磷酸化所必需的。因此，PNUTS和PP 1一起微调DNA损伤后DNA-PKcs的动态磷酸化以介导NHEJ。
DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays a key role in mediating non-homologous end joining (NHEJ), a major repair pathway for DNA double-strand breaks (DSBs). The activation, function and dynamics of DNA-PKcs is regulated largely by its reversible phosphorylation at numerous residues, many of which are targeted by DNA-PKcs itself. Interestingly, these DNA-PKcs phosphorylation sites function in a distinct, and sometimes opposing manner, suggesting that they are differentially regulated via complex actions of both kinases and phosphatases. In this study we identified several phosphatase subunits as potential DSB-associated proteins. In particular, protein phosphatase 1 (PP1) is recruited to a DSB-mimicking substrate in Xenopus egg extracts and sites of laser microirradiation in human cells. Depletion of PP1 impairs NHEJ in both Xenopus egg extracts and human cells. PP1 binds multiple motifs of DNA-PKcs, regulates DNA-PKcs phosphorylation, and is required for DNA-PKcs activation after DNA damage. Interestingly, phosphatase 1 nuclear targeting subunit (PNUTS), an inhibitory regulator of PP1, is also recruited to DNA damage sites to promote NHEJ. PNUTS associates with the DNA-PK complex and is required for DNA-PKcs phosphorylation at Ser-2056 and Thr-2609. Thus, PNUTS and PP1 together fine-tune the dynamic phosphorylation of DNA-PKcs after DNA damage to mediate NHEJ.
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